a) Field of the Invention
This invention relates to novel benzothiazine derivatives. More specifically, this invention is concerned with benzothiazine derivatives and salts thereof, said derivatives and salts being useful for the prevention or treatment of ischemic heart diseases such as angina pectoris, arrhythmia, myocardial infarction, congestive heart, failure and post-PTCA restenosis, cerebrovascular disturbances such as cerebral infarction and cerebral sequelae after subarachnoid hemorrhage, and/or peripheral circulatory disturbances such as arteriosclerosis obliterans, Raynaud disease, Buerger disease and thrombophlebitis; their preparation process; and pharmaceuticals comprising them as effective ingredients.
b) Description of the Related Art
Serotonin is a compound contained abundantly in platelets, which are a blood component, and in a central nervous system, it acts as a neurotransmitter. In platelets, it is released upon stimulation by thromboxane A2, ADP, collagen or the like and synergistically acts on various platelet aggregation factors or vasoconstrictors through activation of serotonin-2 receptors in the platelets and vascular smooth muscle cells, thereby inducing strong platelet aggregation and vasoconstriction [P. M. Vanhoutte, xe2x80x9cJournal of Cardiovascular Pharmacologyxe2x80x9d, Vol. 17 (Supple. 5), S6-S12 (1991)].
Serotonin is also known to potentiate proliferation of vascular smooth muscle cells [S. Araki et al., xe2x80x9cAtherosclerosisxe2x80x9d, Vol. 83, p29-p34(1990)]. It has been considered that, particularly when endothelial cells are injured as in arteriosclerosis or myocardial infarction, the vasoconstricting action and thrombus forming action of serotonin are exasperated, thereby reducing or even stopping blood supply to myocardial, cerebral and peripheral organs [P. Golino et al., xe2x80x9cThe New England Journal of Medicinexe2x80x9d, Vol. 324, No. 10, p641-p648(1991), Y. Takiguchi et al., xe2x80x9cThrombosis and Haemostasisxe2x80x9d, Vol. 68(4), p460-p463(1992), A. S. Weyrich et al., xe2x80x9cAmerican Journal of Physiologyxe2x80x9d, Vol. 263, H349-H358 (1992)].
Being attracted by such actions of serotonin or serotonin-2 receptors, various attempts are now under way to use a serotonin-2 receptor antagonist as a pharmaceutical for ischemic diseases of the heart, the brain and peripheral tissues.
Ketanserin which has therapeutically been used as a hypotensive drug is known as a compound having antagonistic action against a serotonin-2 receptor. Ketanserin has strong antagonistic action against a sympathetic nerve xcex11 receptor and also against histamine-1 and dopamine receptors in addition to antagonistic action against serotonin-2 receptors so that there is the potential problem of developing excessive hypotensive action, neuroleptic action or the like when used for the treatment of ischemic heart disease or peripheral circulatory disturbance. Ketanserin is therefore not preferred.
In addition, several compounds led by sarpogrelate are known to have serotonin-2 receptor antagonistic action. They, however, are accompanied with problems in the potency, the selectivity against other receptors, toxicity, side effects or the like. Thus, there remains still much room for improvements.
In view of the foregoing circumstances, the present inventors synthesized numerous compounds and investigated their pharmacological effects. As a result, it has been found that specific benzothiazine derivatives have strong serotonin-2 receptor antagonistic action, is excellent in the selectivity of a serotonin-2 receptor in the antagonistic action against various receptors, particularly in the selectivity to a serotonin-2 receptor in the antagonistic action against xcex11 receptor, and have low toxicity, leading to the completion of the present invention.
The present invention has been completed based on the above described findings and a first object of the present invention is to provide a benzothiazine derivative represented by the following formula (I): 
wherein the dashed line indicates the presence or absence of a bond and when the bond indicated by the dashed line is present,
Z represents one of the following groups: 
in which R1 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aralkyl group but, when the bond indicated by the dashed line is absent, Z represents one of the following groups: 
wherein R2 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group, R3 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group, R4 represents a hydrogen atom, a substituted or unsubstituted alkyl group or a substituted or unsubstituted aralkyl group, X1, X2 and X3 each independently represents an oxygen atom or a sulfur atom, G represents an ethylene group with one or more of the hydrogen atoms thereof optionally substituted by a like number of halogen atoms and/or alkyl, aryl, aralkyl and/or alkylidene groups or a trimethylene group with one or more of the hydrogen atoms thereof optionally substituted by a like number of halogen atoms and/or alkyl, aryl, aralkyl and/or alkylidene groups,
Q1 represents a hydrogen atom, a hydroxyl group, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aralkyloxy group,
Q2 represents a hydrogen atom, a hydroxyl group, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aralkyloxy group,
A represents a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group,
Y represents CH, Cxe2x95x90 or a nitrogen atom; and, when Y represents CH, m stands for 0 or 1, n stands for 1 or 2, and B represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group, a sulfonyl group, an alkylene group, an alkenylene group, a substituted or unsubstituted hydroxymethylene group, a group xe2x80x94CHR5xe2x80x94 in which R5 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cyclic or acyclic acetal group, when Y represents Cxe2x95x90, m stands for 1, n stands for 1 or 2, and B represents: 
in which the double bond is linked to Y, R6 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group, but, when Y represents a nitrogen atom, m stands for 0 or 1, n stands for 2 or 3, and B represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group xe2x80x94CHR7xe2x80x94 in which R7 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group,
E1 and E2 each independently represents a hydrogen atom or a lower alkyl group, and
D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group; or a salt thereof.
Another object of the present invention is to provide a preparation process of the benzothiazine derivative (I) or its salt.
A further object of the present invention is to provide a pharmaceutical such as a therapeutic for circulatory diseases or the like, said pharmaceutical containing the benzothiazine derivative (I) or its pharmacologically-acceptable salt thereof as an effective ingredient.
The benzothiazine derivatives (I) and their salts according to the present invention have strong serotonin-2 blocking action, have excellent selectivity to xcex11 blocking action and have high safety. Accordingly, the present invention has made it possible to provide pharmaceuticals making use of antagonistic action against serotonin-2 receptors, for example, therapeutics for various circulatory diseases such as ishemic heart diseases, cerebrovascular disturbance and peripheral circulatory disturbance.
In the benzothiazine derivatives (I) of the present invention, preferred examples of group R1 include branched or linear C1-4 alkyl groups such as methyl and ethyl and C7-22 aralkyl groups such as benzyl and phenethyl, each of which may be substituted by one or more of halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; and/or alkoxy groups, preferably C1-4 alkoxy groups such as methoxy and ethoxy.
Preferred examples of group R2 include branched or linear C1-4 alkyl groups such as methyl and ethyl, C6-14 aryl groups such as phenyl and naphtyl and C7-22 aralkyl groups such as benzyl and phenethyl, each of which may be substituted by one or more of halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; and/or alkoxy groups, preferably C1-4 alkoxy groups such as methoxy and ethoxy. In this case, preferred examples of group R2X1xe2x80x94include methoxy, methylthio, ethoxy and ethylthio groups.
Preferred examples of the following group: 
includes groups represented by the following formulas: 
in which one or more of the hydrogen atoms may be substituted by a corresponding number of halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; aryl groups, preferably C6-14 aryl groups such as phenyl and naphtyl; aralkyl groups, preferably C7-22 aralkyl groups such as benzyl and phenethyl; and/or alkylidene groups, preferably C1-4 alkylidene groups such as methylidene and ethylidene.
Preferred examples of group R3 of group NOR3 include a hydrogen atom, branched or linear C1-4 alkyl groups such as methyl and ethyl, C6-14 aryl groups such as phenyl and naphtyl and C7-22 aralkyl groups such as benzyl and phenethyl. Each of the exemplified groups may be substituted by one or more of halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; and/or alkoxy groups, preferably C1-4 alkoxy groups such as methoxy and ethoxy.
Preferred examples of group R4 include a hydrogen atom, branched or linear C1-4 alkyl groups such as methyl and ethyl and C7-22 aralkyl groups such as benzyl and phenethyl. Each of the exemplified groups may be substituted by one or more of halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; and/or alkoxy groups, preferably C1-4 alkoxy groups such as methoxy and ethoxy.
Preferred examples of group Z include the following group: 
Specifically preferred examples of the group Z include the following groups: 
wherein G, R1, R2, R4, X1, X2 and X3 have the same meanings as defined above.
Preferred examples of Q1 include a hydrogen atom; a hydroxyl group; halogen atoms such as fluorine, chlorine and bromine; branched or linear C1-4 alkyl groups such as methyl and ethyl; branched or linear C1-4 alkoxy groups such as methoxy and ethoxy; C7-22 aralkyl groups such as benzyl and phenethyl; and C7-22 aralkyloxy groups such as benzyloxy and phenethyloxy. Each of the exemplified groups may be substituted by one or more of halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; and/or alkoxy groups, preferably C1-4 alkoxy groups such as methoxy and ethoxy. Of these Q1 particularly preferred include a hydrogen atom, a methoxy group, a chlorine atom and the like.
Preferred examples of Q2 include a hydrogen atom; a hydroxyl group; halogen atoms such as fluorine, chlorine and bromine; branched or linear C1-4 alkyl groups such as methyl and ethyl; branched or linear C1-4 alkoxy groups such as methoxy and ethoxy; C7-22 aralkyl groups such as benzyl and phenethyl; and C7-22 aralkyloxy groups such as benzyloxy and phenethyloxy. Each of the exemplified groups may be substituted by one or more of halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; and/or alkoxy groups, preferably C1-4 alkoxy groups such as methoxy and ethoxy. Of these Q2, particularly preferred include a hydrogen atom, a methoxy group, a chlorine atom and the like.
Further, preferred examples of substituting positions and combinations of Q1 and Q2 include combinations of a hydrogen atom as Q1 and 5-hydroxy, 5-chloro, 5-bromo, 5-methyl, 5-ethyl, 5-n-propyl, 5-isopropyl, 5-n-butyl, 5-s-butyl, 5-methoxy, 5-ethoxy, 5-n-propoxy, 5-isopropoxy, 5-benzyloxy, 6-hydroxy, 6-fluoro, 6-chloro, 6-methyl, 6-ethyl, 6-n-propyl, 6-methoxy, 6-ethoxy, 6-n-propoxy, 6-benzyloxy, 7-hydroxy, 7-fluoro, 7-chloro, 7-methyl, 7-ethyl, 7-n-propyl, 7-methoxy, 7-ethoxy, 7-n-propoxy, 7-benzyloxy, 8-hydroxy, 8-fluoro, 8-chloro, 8-methyl, 8-ethyl, 8-n-propyl, 8-methoxy, 8-ethoxy, 8-n-propoxy and 8-benzyloxy as Q2; and also combinations of 5,7-dihydroxy, 6,7-dichloro, 5,8-dimethyl, 6,8-dimethyl, 5,6-dimethoxy, 5,7-dimethoxy, 5,8-dimethoxy and 6,7-dimethoxy as Q1 and Q2.
Preferred examples of group A include branched or linear C2-10 alkylene groups such as ethylene, trimethylene, tetramethylene, pentamethylene and octamethylene, branched or linear C4-10 alkenylene groups such as 2-butenylene and 3-pentenylene groups; and branched or linear C4-10 alkynylene groups such as 2-butynylene and 3-pentynylene groups. Each of the exemplified group may be substituted by one or more of halogen atoms such as fluorine, chlorine and bromine. Among them, ethylene, trimethylene and tetramethylene groups are particularly preferred.
The group, which is represented by the following formula: 
wherein E1, E2, Y and n have the same meanings as defined above, is a heterocyclic group led by a pyrrolidine, piperidine, piperazine or homopiperazine group, in which two or less hydrogen atoms on the ring may be substituted by lower alkyl groups, preferably C1-4 alkyl groups such as methyl or ethyl.
When the group of the above formula is a heterocylic group derived from pyrrolidine or piperidine, preferably a piperidine group, m stands for 0 or 1 with the proviso that m is 1 when Y represents Cxe2x95x90, and B represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group, a sulfonyl group, an alkylene group (preferably a C1-4 alkylene group and most preferably a methylene group), an alkenylene group (preferably C2-5 alkenylene group and most preferably a 2-propenylene group), a substituted or unsubstituted hydroxymethylene group, a group xe2x80x94CHR5xe2x80x94 (in which R5 preferably represents a C1-4 alkyl group such as methyl and ethyl; a C6-14 aryl group such as phenyl or naphthyl; or a C7-22 aralkyl group such as benzyl or phenethyl, which may be substituted), the following group: 
wherein the double bond is linked to Y, and R6 represents an alkyl group, preferably a C1-4 alkyl group such as methyl and ethyl; an aryl group, preferably C6-14 aryl group such as phenyl and naphtyl; and an aralkyl group, preferably a C7-22 aralkyl group such as benzyl and phenethyl, which may be substituted), cyclic acetal or acyclic acetal group in which one or more of hydrogen atoms may be substituted.
Exemplary cyclic or acylic acetal groups include the following groups: 
Preferred examples of a substituent group for the hydroxylmethylene group represented by B include alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl and aryl groups, preferably C6-14 aryl groups such as phenyl and naphthyl, all substituted to the carbon atom of the methylene group. Further, they can be substituted by one or more of hydroxyl groups, halogen atoms such as fluorine, chlorine and bromine and/or alkoxy groups, preferably C1-4 alkoxy groups such as methoxy and ethoxy.
Particularly preferred examples of the substituted or unsubstituted hydroxymethylene group include an unsubstituted hydroxymethylene group and hydroxymethylene groups substituted by a phenyl, fluorophenyl or hydroxyphenyl group.
Further, examples of one or more substituent groups for R5 include one or more halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; and alkoxy groups, preferably C1-4 alkoxy groups such as methoxy and ethoxy.
Illustrative of one or more substituent groups for R6 include one or more halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; alkoxy groups, preferably C1-4 alkoxy groups such as methoxy and ethoxy; and hydroxyl groups. Examples of one or more substituent groups for the cyclic or acyclic acetal include halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; aryl groups, preferably C6-14 aryl groups such as phenyl and naphthyl; aralkyl groups, preferably C7-22 aralkyl groups such as benzyl and phenethyl; and alkylidene groups, preferably C1-4 alkylidene groups such as methylidene and ethylidene.
Among these illustrative examples of the group represented by B, especially preferred is a carbonyl group.
When the heterocyclic group is a group derived from piperazine or homopiperazine, preferably a piperazine group, m stands for 0 or 1 (preferably 0) and B represents a carbonyl group, a sulfonyl group, an alkylene group (preferably a C1-4 alkylene group, particularly a methylene group), an alkenylene group (preferably C3-6 alkenylene group, particularly 2-propenylene group) or a group xe2x80x94CHR7xe2x80x94 (in which R7 represents an alkyl group, preferably a C1-4 alkyl group such as methyl and ethyl; an aryl group, preferably C6-14 aryl group such as phenyl and naphtyl; and an aralkyl group, preferably a C7-22 aralkyl group such as benzyl and phenethyl).
R7 may in turn be substituted by one or more halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; and/or alkoxy groups, preferably C1-4 alkoxy groups such as methoxy and ethoxy.
Of the above-described examples of group B, preferred is a substituted or unsubstituted phenylmethylene group.
Preferred examples of group D include aromatic hydrocarbon groups, preferably C6-28 aromatic hydrocarbon groups such as a phenyl group with one or more of its hydrogen atoms having been optionally substituted and a naphtyl group with one or more of its hydrogen atoms having been optionally substituted. Other preferred examples of group D include aromatic heterocyclic groups, preferably monocyclic or bicyclic ones with three or fewer oxygen, sulfur and/or nitrogen atomsxe2x80x94such as pyridyl, pyrimidinyl, benzisothiazolyl, benzisoxazolyl and indolyl groups with one or more hydrogen atoms thereof having been optionally substituted.
Examples of substituent groups for the aromatic hydrocarbon groups and aromatic heterocyclic groups include halogen atoms such as fluorine, chlorine and bromine; alkyl groups, preferably C1-4 alkyl groups such as methyl and ethyl; alkoxy groups, preferably C1-4 alkoxy groups such as methoxy and ethoxy; aryl groups, preferably C6-14 aryl groups such as phenyl and naphtyl; aralkyl groups, preferably C7-22 aralkyl groups such as benzyl and phenethyl; aralkyloxy groups, preferably C7-22 aralkyloxy groups such as benzyloxy; cyano group; nitro group; carboxyl group; alkoxycarbonyl group (the number of carbons in the alcohol moiety preferably ranges from 1 to 6); lower alkylsulfonylamino groups (the number of carbon atoms in the alkyl moiety preferably ranges from 1 to 4); a carbamoyl group; and a hydroxyl group.
Of these illustrative groups represented by D, preferred are phenyl groups unsubstituted or substituted by one or more of halogen atoms, alkoxy groups and hydroxyl groups, benzisothiazolyl groups unsubstituted or substituted by one or more halogen atoms, benzisoxazolyl groups unsubstituted or substituted by one or more halogen atoms, and indazolyl groups unsubstituted or substituted by one or more halogen atoms. Particularly preferred are phenyl groups unsubstituted or substituted by one or more of fluorine atoms, methoxy groups and hydroxyl groups.
Many of the compounds (I) according to the present invention have isomers. It is to be noted that these isomers and mixtures thereof are all embraced by the present invention.
Various processes can be employed for the preparation of the benzothiazine derivatives (I) according to the present invention. It is however preferred to prepare the benzothiazine derivatives, for example, by any one of the following processes.
Process 1:
Among the benzothiazine derivatives (I), each of compounds (Ib) in which Z is represented by one of the following formulas: 
can be synthesized in accordance with any of the processes shown by the following schemes.
(a) The compound (Ib) can be obtained, in accordance with the following reaction scheme, by reacting a compound represented by the formula (XXV) with a compound represented by the formula (III) to be converted to a compound represented by the formula (XXVI) and then reacting a nitrogen-containing compound represented by the formula (V) or a salt thereof with the compound (XXVI). 
wherein A, B, D, E1, E2, Q1, Q2, Y, m and n have the same meanings as defined above, Z2 represents one of the following groups: 
wherein G, R2, X1, X2 and X3 have the same meanings as defined above, and W and Wxe2x80x2 may be the same or different and individually represent a substituent easily replaceable with an amino group.
In the above reactions, the conversion from the compound (XXV) to the compound (XXVI) can be effected by causing the compound (III) to act on the compound (XXV) after treating the compound (XXV) with an inorganic base or an organic base, or by causing the compound (III) to act on the compound (XXV) in the presence of such a base.
Examples of group W or Wxe2x80x2 of the compound (III), which is an eliminative substituent and is easily replaceable with an amino group, include halogen atoms such as chlorine and bromine, alkylsulfonyloxy groups such as methanesulfonyloxy and arylsulfonyloxy groups such as p-toluenesulfonyloxy.
On the other hand, exemplary inorganic or organic bases include sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, triethylamine and potassium t-butoxide. Further, illustrative solvents useful for the above reaction include tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, N-methylpyrrolidone, acetone, 2-butanone and toluene. The reaction is conducted at xe2x88x9278xc2x0 C. to reflux temperature.
To prepare the compound (Ib) by reacting the thus-obtained compound (XXV) with the nitrogen-containing compound (V), it is only necessary to react the nitrogen-containing compound (V) or an organic acid salt or inorganic acid salt thereof with the compound (XXV), optionally together with an organic base such as triethylamine, pyridine, collidine, 1,8-diazabicyclo-[5.4.0]undec-7-en (DBU) or potassium t-butoxide or an inorganic base such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide or sodium hydride, optionally after adding an alkali iodide such as potassium iodide or sodium iodide, at 0xc2x0 C. to 150xc2x0 C. in the solvent exemplified above or a solvent such as methanol, ethanol, propanol or butanol.
Examples of the nitrogen-containing compound (V) include 1-phenylpiperazine, 1-(2-fluorophenyl)piperazine, 1-(3-fluorophenyl)piperazine, 1-(4-fluorophenyl)piperazine, 1-(4-hydroxyphenyl)piperazine, 1-(2-chlorophenyl)piperazine, 1-(3-chlorophenyl)piperazine, 1-(4-chlorophenyl)piperazine, 1-(2-methoxyphenyl)piperazine, 1-(3-methoxyphenyl)piperazine, 1-(4-methoxyphenyl)piperazine, 1-(4-methanesulfonamidophenyl)piperazine, 1-(4-cyanophenyl)piperazine, 1-(4-carbamoylphenyl)piperazine, 1-(4-methoxycarbonylphenyl)piperazine, 1-(2-pyridyl)piperazine, 1-(2-pyrimidinyl)piperazine, 1-benzylpiperazine, 1-diphenylmethylpiperazine, 1-cinnamylpiperazine, 1-benzoylpiperazine, 1-(4-benzyloxybenzoyl)piperazine, 1-(4-hydroxybenzoyl)piperazine, 1-(2-furoyl)piperazine, 1-(1,2-benzisooxazol-3-yl)piperazine, 1-(1,2-benzisothiazol-3-yl)piperazine, 4-phenylpiperidine, 4-benzylpiperidine, xcex1,xcex1-bis(4-fluorophenyl)-4-piperidinemethanol, 4-(4-fluorobenzoyl)piperidine, 4-benzoylpiperidine, 4-(4-methoxybenzoyl)piperidine, 4-(4-chlorobenzoyl)piperidine, 3-(4-fluorobenzoyl)piperidine, 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine, 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidine, 4-(6-fluoro-1H-indazol-3-yl)piperidine, 3-benzoylpyrrolidine, 3-(4-fluorobenzoyl)pyrrolidine, 4-(4-fluorophenoxy)piperidine, 4-[(4-fluorophenyl)thio]piperidine, 4-[(4-fluorophenyl)sulfinyl]piperidine, 4-[(4-fluorophenyl)sulfonyl]piperidine, 4-[bis(4-fluorophenyl)methylene]piperidine and 4-(4-fluorobenzoyl)piperidine ethylene acetal. They are all either known compounds or compounds which can be readily prepared by a known process or a process similar to the known process.
In the above reactions, the compound (XXV) employed as the starting material can be prepared using as a raw material a saccharin derivative represented by the formula (XXVII) in accordance with the following reaction scheme: 
wherein G, R2, Q1, Q2, X1, X2, X3 and Z2 have the same meanings as defined above.
Saccharins (XXVII) usable as starting materials in the above reactions are either known compounds or compounds which can be readily prepared by a known process or by referring to known literature. For example, preparation processes for saccharins substituted by one or more hydroxyl groups are disclosed in Japanese Patent Application Laid-Open (Kokai) No. SHO 56-166181, Japanese Patent Application Laid-Open (Kokai) No. SHO 61-215382, etc., while preparation processes for saccharins substituted by one or more halogen atoms such as fluorine, chlorine and bromine atoms were proposed, for example, by W. Davies in J. Chem. Soc., 119(I), 876 (1921), by F. Becke et al. in Liebigs Ann. Chem., 729, 146 (1969), by J. G. Lombardino in J. Org., Chem., 36, 1843 (1971) and by Nitta et al. in Yakugaku Zasshi, 84, 496 (1964) and are also disclosed in Japanese Patent Application Laid-Open (Kokai) No. SHO 52-71464, Japanese Patent Application Laid-Open (Kokai) No. SHO 56-166181, Japanese Patent Application Laid-Open (Kokai) No. HEI 5-194444, etc.
Further, preparation processes for saccharins substituted by one or more alkyl groups such as methyl groups were proposed by J. G. Lombardino in J. Org. Chem., 36, 1843 (1971) and are disclosed in Japanese Patent Application Laid-Open (Kokai) No. SHO 52-71464, Japanese Patent Application Laid-Open (Kokai) No. SHO 61-215382, Japanese Patent Application Laid-Open (Kokai) No. HEI 5-194444, etc., and preparation processes for saccharins substituted by one or more alkoxy groups such as methoxy groups were proposed by J. G. Lombardino in J. Org. Chem., 36, 1843 (1971) and are disclosed in Japanese Patent Application Laid-Open (Kokai) No. SHO 52-71464, Japanese Patent Application Laid-Open (Kokai) No. SHO 56-166181, Japanese Patent Application Laid-Open (Kokai) No. SHO 61-263961, Japanese Patent Application Laid-Open (Kokai) No. HEI 5-194444, etc.
Accordingly, saccharins (XXIII) containing desired substituent groups as Q1 and Q2 can be obtained by these processes or by processes derived with reference to such processes.
The conversion from the compound (XXVII) to the compound (XXVxe2x80x2) can be conducted referring to literatures [E. Eckenroth et al., Ber., 29, 329 (1896); H. Zinnes et al., J. Org. Chem., 30, 2241 (1965); H. Zinnes et al., J. Org. Chem., 31, 162 (1966)].
On the other hand, the conversion from the compound (XXVxe2x80x2) to the compound (XV) can be effected using various processes. As a typical example, an acid such as hydrochloric acid or acetic acid is caused to act on the compound (XXVxe2x80x2).
Further, the conversion from the compound (XV) to the compound (XXV) can be conducted by choosing an appropriate process such as that described by T. W. Greene in Protective Groups in Organic Synthesis, John Wiley and Sons, Inc. As a typical example, R2X1H or HX2-G-X3H is caused to act on the compound (XV) in the presence of an acid.
In addition, the compound (XXVI) can also be synthesized from the compound (XXVxe2x80x2) in accordance with the following reaction scheme. 
wherein A, G, Q1, Q2, R2, W, Wxe2x80x2, X1, X2, X3 and Z2 have the same meanings as defined above.
The conversion from the compound (XXVxe2x80x2) to the compound (XXVIxe2x80x2) can be practiced under similar conditions as the conversion from the compound (XXV) to the compound (XXVI). Further, the conversion from the compound (XXVIxe2x80x2) to the compound (VIII) can be practiced under similar conditions as the conversion from the compond (XXVxe2x80x2) to the compound (XV). Moreover, the conversion from the compound (VIII) to the compound (XXVI) can be practiced under similar conditions as the conversion from the compound (XVxe2x80x2) to the compound (XXV)
(b) The target compound can be obtained by causing a nitrogen-containing compound represented by the formula (VI) or a salt thereof to act on the compound represented by the formula (XXV) in accordance with the following reaction scheme: 
wherein A, B, D, E1, E2, Q1, Q2, W, Y, Z2, m and n have the same meanings as defined above.
The conversion from the compound (XXV) to the compound (Ib) can be conducted by causing the compound (VI) to act on the compound (XXV) after treatment of the latter compound with an inorganic base or an organic base or in the presence of such a base. Reaction conditions are similar to those employed in the conversion from the compound (XXV) to the compound (XXVI) in Process 1(a). In this case, it is also possible to add an alkali iodide such as potassium iodide or sodium iodide as needed. Incidentally, the compound (VI) can be synthesized by reacting the compound (V) with the compound (III) in a manner known per se in the art.
Process 2:
Among the benzothiazine derivatives (I), each of compounds (Ic) in which Z is represented by the following formula: 
can be synthesized in any one of the following processes.
(a) The target compound can be obtained, in accordance with the following reaction scheme, by converting a compound (XV) or (XXVI) to a compound (VIII) and then reacting the compound (VIII) with a compound represented by the formula (V): 
wherein A, B, D, E1, E2, Q1, Q2, W, Wxe2x80x2, Y, Z2, m and n have the same meanings as defined above.
The conversion from the compound (XV) to the compound (VIII) can be effected under conditions similar to those employed upon conversion from the compound (XXV) to the compound (XXVI) shown in Process 1(a). Further, the conversion from the compound (XXVI) to the compound (VIII) can be effected employing the process described by T. W. Greene in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, Inc. and the like. For instance, the conversion to the target compound (VIII) can be conducted by acid treatment of the compound (XXVI) when in Z2, X1 represents an oxygen atom or X2 and X3 both represent an oxygen atom, or by the treatment with mercury (II) chloride when X1 represents a sulfur atom or X2 and X3 both represent a sulfur atom.
The conversion from the compound (VIII) to the compound (Ic) can be effected under conditions similar to those employed upon conversion from the compound (XXVI) to the compound (Ib) shown in Process 1(a).
(b) The target compound can be obtained by the conversion of the group Z2 of the compound (Ib) to a carbonyl group in accordance with the following reaction scheme. 
wherein A, B, D, E1, E2, Q1, Q2, Y, Z2, m and n have the same meanings as defined above.
The conversion from the compound (Ib) to the compound (Ic) can be effected under conditions similar to those employed in the conversion from the compound (XXVI) to the compound (VIII) shown in Process 2(a).
Process 3:
Among the benzothiazine derivatives (I), each of the compounds (Ig) and (Ie) in which Z is represented by the following formula: 
can be synthesized in accordance with any one of the following processes. Selection of process (a) is desired where a nitrogen-containing compound (V) contains a group reactive to a hydroxylamine or a derivative thereof (VII) or a salt of the hydroxylamine or the derivative.
(a) Each compound (Ig) can be obtained, in accordance with the following reaction scheme, by causing a hydroxylamine or a derivative thereof represented by the formula (VII) or a salt of the hydroxylamine or the derivative thereof to act on the compound represented by the formula (VIII) and then causing the nitrogen-containing compound (V) to act further. 
wherein A, B, D, E1, E2, Q1, Q2, R3, W, Y, m and n have the same meanings as defined above.
The reaction between the compound (VIII) and the hydroxylamine or its derivative (VII) can be practiced, if necessary, in the presence of an organic base such as pyridine, triethylamine, collidine, DBU or sodium acetate or an inorganic base such as potassium carbonate or sodium hydroxide. The hydroxylamine or its derivative (VII) may also be used in the form of an organic acid salt or an inorganic acid salt.
The reaction is conducted at 0xc2x0 C. to reflux temperature, preferably 0xc2x0 C. to 100xc2x0 C. optionally in a suitable solvent such as methanol, ethanol, propanol, tetrahydrofuran, dimethylformamide or dimethylsulfoxide.
The conversion from the thus-obtained compound (IX) to the compound (Ig) can be effected under conditions similar to those employed in the conversion from the compound (XXVI) to the compound (Ib) shown in Process 1(a).
(b) Each compound (Ie) can be obtained, in accordance with the following reaction scheme, by causing a hydroxylamine or a derivative thereof (VII) or a salt of the hydroxylamine or the derivative to act on the compound (Id): 
wherein, when Y represents CH, Bxe2x80x2 represents an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, an alkylene group, an alkenylene group, a substituted or unsubstituted hydroxymethylene group, a group xe2x80x94CHR5xe2x80x94 in which R5 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cyclic or acyclic acetal group, when Y represents Cxe2x95x90, Bxe2x80x2 represents the following group: 
in which the double bond is linked to Y, R6 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group, but, when Y represents a nitrogen atom, Bxe2x80x2 represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group xe2x80x94CHR7xe2x80x94 in which R7 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group, and A, D, E1, E2, Q1, Q2, R3, Y, m and n have the same meanings as defined above.
The conversion from the compound (Id) to the compound (Ie) can be effected under conditions similar to those employed in the conversion from the compound (VIII) to the compound (IX) shown in Process 3(a).
Process 4:
Among the benzothiazine derivatives (I), each of compounds (Ih) and (If) in which Z is represented by the following formula: 
can be synthesized by any one of the following processes.
Incidentally, it is desired to select process (a) when there is a group reactive with a reducing agent in a nitrogen-containing compound (V).
(a) Each compound (Ih) can be obtained, in accordance with the following reaction scheme, by reducing the compound represented by the formula (VIII) to obtain the compound (X) and then causing the nitrogen-containing compound (V) to act on the resulting compound. 
wherein A, B, D, E1, E2, Q1, Q2, W, Y, m and n have the same meanings as defined above.
The conversion from the compound (VIII) to the compound (X) can be effected by treating the compound represented by the formula (VIII) with a reducing agent such as sodium borohydride, potassium borohydride or sodium cyanoborohydride in a conventionally-employed solvent at xe2x88x9278xc2x0 C. to reflux temperature, preferably xe2x88x9220xc2x0 C. to room temperature.
Further, the conversion from the compound (X) to the compound (Ih) can be effected under conditions similar to those employed in the conversion from the compound (XXVI) to the compound (Ib) shown in Process 1(a).
(b) Each compound (If) can be obtained by reducing the compound (Id) in accordance with the following reaction scheme: 
wherein A, Bxe2x80x2, D, E1, E2, Q1, Q2, Y, m and n have the same meanings as defined above.
The conversion from the compound (Id) to the compound (If) can be effected under conditions similar to those employed in the conversion from the compound (VIII) to the compound (X) shown in Process 4(a).
Process 5:
Among the benzothiazine derivatives (I), each compound (Il) in which Z is a group represented by the following formula: 
can be synthesized in accordance with the process which will be described hereinafter:
The target compound can be obtained, in accordance with the following reaction scheme, by reacting a compound represented by the formula (XV) with a compound represented by the formula (XVI) to obtain a compound represented by the formula (XVII), reacting the resulting compound with a compound represented by the formula (III) to obtain a compound represented by the formula (XXX), and then causing a nitrogen-containing compound represented by the formula (V) to act on the compound (XXX). 
wherein A, B, D, E1, E2, Q1, Q2, R1, W, Wxe2x80x2, Y, m and n have the same meanings as defined above.
In the above reaction, the conversion from the compound (XV) to the compound (XVII) can be effected by causing the compound (XVI) to act on the compound (XV) in the presence of p-toluenesulfonic acid, boron trifluoride ethyl ether complex, Amberlite 15 or the like.
Examples of the solvent usable in the above reaction may include methanol, ethanol, propanol and butanol. The reaction can be conducted at xe2x88x9278xc2x0 C. to reflux temperature.
Further, the conversion from the compound (XVII) to the compound (Il) can be effected under conditions similar to those employed in the conversion from the compound (XXV) to the compound (Ib) shown in Process 1(a).
Process 6:
Among the benzothiazine derivatives (I), each compound (Ii) in which Z is represented by the following formula: 
can be synthesized in accordance with the process which will be described hereinafter.
The compound represented by the formula (Ii) can be obtained, in accordance with the following reaction scheme, (1) by reducing a compound represented by the formula (XXXI) to a compound represented by the formula (XXXII) and reacting the resulting compound with the compound represented by the formula (III), or (2) by reacting a compound represented by the formula (XI) with a compound represented by the formula (X) to obtain a compound (XII), and then reacting the resulting compound with a nitrogen-containing compound represented by the formula (V). In this case, it is desired to select a suitable process from the processes (1) and (2) according to the kind of group R8. 
wherein A, B, D, E1, E2, Q1, Q2, R8, W, Wxe2x80x2, Wxe2x80x3, Y, m and n have the same meanings as defined above.
In the above reaction, the conversion from the compound (XXXI) to the compound (XXXII) can be conducted by treating, in the presence of a catalyst such as palladium-carbon or platinum, the compound (XXXI) with hydrogen gas in a conventionally-employed solvent at xe2x88x9278xc2x0 C. to reflux temperature, preferably at room temperature. The conversion from the compound (XXXII) to the compound (XII) can be effected under conditions similar to those employed in the conversion from the compound (XXV) to the compound (XXVI) shown in Process 1(a).
The conversion from the compound (X) to the compound (XII) can be conducted by causing the compound (XI) to act on the compound (X) either after treatment of the compound (X) with an inorganic base or organic base or in the presence of such a base.
The group Wxe2x80x3 in the compound (XI) is an eliminative substituent, and its examples include halogen atoms such as chlorine and bromine, alkylsulfonyloxy groups such as methanesulfonyloxy and arylsulfonyloxy groups such as p-toluenesulfonyloxy.
Further, exemplary inorganic or organic bases usable in the above reaction include sodium hydride, sodium bis(trimethylsilyl)amide, lithium diisopropylamide and potassium t-butoxide. Illustrative solvents usable in the present reaction include, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and toluene. The reaction may be conducted at xe2x88x9278xc2x0 C. to reflux temperature.
The conversion from the compound (XII) to the compound (Ii) can be effected under conditions similar to those employed upon conversion from the compound (XXVI) to the compound (Ib) in Process 1(a).
Process 7:
Among the benzothiazine derivatives (I), each compound (Ij) in which Z is represented by the following formula: 
can be synthesized in accordance with the process which will be described hereinafter.
The compound represented by the formula (Ij) can be obtained, in accordance with the following reaction scheme, by subjecting a compound represented by the formula (X) to dehydration to obtain a compound represented by the formula (XIII) and then causing a nitrogen-containing compound represented by the formula (V) to act on the resultant compound. 
wherein A, B, D, E1, E2, Q1, Q2, W, Y, m and n have the same meanings as defined above.
In the above reactions, the conversion from the compound (X) to the compound (XIII) is conducted by causing methyanesulfonyl chloride or p-toluenesulfonyl chloride and a base such as triethylamine, pyridine or collidine to act on the compound (X) in a solvent such as dichloromethane, chloroform or toluene and then treating the reaction product with the above base or silica gel at room temperature to reflux temperature.
Further, the conversion from the compound (XIII) to the compound (Ij) can be conducted under conditions similar to the conversion from the compound (XXVI) to the compound (Ib) shown in Process I(a).
Process 8:
Among the benzothiazine derivatives (I), each compound (Ik) in which Z is represented by the following formula: 
can be synthesized in accordance with the process which will be described hereinafter.
The compound represented by the formula (Ik) can be obtained, in accordance with the following reaction scheme, by subjecting a compound represented by the formula (XIII) to reduction to obtain a compound represented by the formula (XIV) and then reacting the resultant compound with a nitrogen-containing compound represented by the formula (V). 
wherein A, B, D, E1, E2, Q1, Q2, W, Y, m and n have the same meanings as defined above.
In the above reactions, the conversion from the compound (XIII) to the compound (XIV) can be conducted in a manner similar to the conversion from the compound (XXXI) to the compound (XXXII) in Process 6.
Further, the conversion from the compound (XIV) to the conversion (Ik) can be conducted under conditions similar to those employed in the conversion of the compound (XXVI) to the compound (Ib) shown in Process 1(a).
The compounds (I) of the present invention obtained according to the above-described processes can each be reacted with one of various acids to convert the compound to its salt. The salt can be purified by a method such as recrystallization or column chromatography.
Exemplary acids usable to convert the benzothiazine derivatives (I) to their salts include inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and hydrobromic acid; and organic acids such as maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid and tannic acid.
As will be demonstrated later by tests, the benzothiazine derivatives (I) and their salts according to the present invention, which can be obtained as described above, have a strong serotonin-2 blocking action and in addition, they have excellent selectivity to xcex11 blocking action. Further, as a result of a toxicity test, they have been found to feature high safety. The compounds according to the present invention can therefore be used as therapeutics for circulatory diseases such as ischemic heart diseases, cerebrovascular disturbances and peripheral circulatory disturbances.
When the benzothiazine derivative (I) according to this invention are used as drugs, they can be administered in an effective dose as they are. As an alternative, they can also be formulated into various preparation forms by known methods and then administered.
Exemplary preparation forms as drugs include orally administrable preparation forms such as tablets, powders, granules, capsules and syrups as well as parenterally administrable preparation forms such as injections and suppositories. Whichever preparation form is used, a known liquid or solid extender or carrier usable for the formulation of the preparation form can be employed.
Examples of such extender or carrier include polyvinylpyrrolidone, arabic gum, gelatin, sorbit, cyclodextrin, tragacanth gum, magnesium stearate, talc, polyethylene glycol, polyvinyl alcohol, silica, lactose, crystalline cellulose, sugar, starch, calcium phosphate, vegetable oil, carboxymethylcellulose, sodium laurylsulfate, water, ethanol, glycerin, mannitol, syrup, and the like.
When the compounds (I) according to the present invention are used as drugs, their dose varies depending on the administration purpose, the age, body weight and conditions of the patient to be administered, etc. In oral administration, the daily dose may generally be about 0.01-1,000 mg.
The present invention will next be described in further detail by the following examples and tests. It is however borne in mind that the present invention is not limited to the following examples and tests.